tbuckley/cabot-search huggingface dataset:
AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors
Authors: Sophia Frentzas, Steven Kao, Rang Gao, Hao Zheng, Ahsan Rizwan, Nageshwar Budha, Luz de la Hoz Pedroza, Wei Tan, Tarek Meniawy
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Ociperlimab, a novel, humanized monoclonal antibody (mAb), binds to T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) with high affinity and specificity. Tislelizumab is an anti-programmed cell death protein 1 mAb. We report results from a phase I, first-in-human, dose escalation study evaluating the safety, pharmacokinetics (PK), and preliminary antitumor activity of ociperlimab plus tislelizumab in patients with advanced solid tumors. Methods Eligible patients previously treated with standard systemic therapy, or for whom treatment was not available or tolerated, received ociperlimab intravenously on Cycle (C) 1 Day (D) 1 and tislelizumab 200 mg intravenously on C1 D8. If tolerated, patients received ociperlimab plus tislelizumab 200 mg sequentially on D29 and every 3 weeks (Q3W) thereafter until discontinuation. Dose escalation for ociperlimab was planned with four dose levels (50 mg, 150 mg, 450 mg, and 900 mg) according to a 3+3 design. An additional dose level of ociperlimab 1800 mg was also assessed. Primary endpoints were safety, determination of the maximum tolerated (or administered) dose, and the recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), duration of response (DoR), disease control rate (DCR) (Response Evaluation Criteria in Solid Tumors version 1.1), PK, and biomarker analysis. Results At data cut-off (September 29, 2022), 32 patients had received ≥1 dose of ociperlimab plus tislelizumab 200 mg Q3W. The maximum administered dose was ociperlimab 1800 mg plus tislelizumab 200 mg Q3W. The median age of enrolled patients was 59.5 years (range: 31–79). Most patients (96.9%) experienced ≥1 treatment-emergent adverse event (TEAE); 62.5% of patients experienced ≥grade 3 TEAEs and 50.0% of patients experienced serious TEAEs. No dose limiting toxicity events were reported. The maximum tolerated dose was not reached. The RP2D was ociperlimab 900 mg plus tislelizumab 200 mg Q3W. Overall, ORR was 10.0%, median DoR was 3.6 months, and DCR was 50.0%. Conclusions Ociperlimab plus tislelizumab was well tolerated in patients with advanced solid tumors, and preliminary antitumor activity was observed with 450 mg, 900 mg, and 1800 mg ociperlimab. Phase II/III trials of ociperlimab 900 mg plus tislelizumab 200 mg Q3W are underway in a range of solid tumors. Trial registration number NCT04047862 .
Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy
Authors: Analena Handke, Claudia Kesch, Wolfgang Peter Fendler, Tugce Telli, Yang Liu, Alexander Hakansson, Elai Davicioni, Jason Hughes, Hong Song, Katharina Lueckerath, Ken Herrmann, Boris Hadaschik, Robert Seifert
Journal: Journal for ImmunoTherapy of Cancer (2023)

Rationale 177 Lu-PSMA ([ 177 Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant 177 Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and 177 Lu-PSMA therapy efficacy is poorly understood. Methods Between March 2018 and December 2021, a total of 168 patients were referred to 177 Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication. Results In the subset of patients who received 177 Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=−0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01). Conclusion Higher PD-L2 signature might be associated with a better response to 177 Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.
Vaccination with post-translational modified, homocitrullinated peptides induces CD8 T-cell responses that mediate antitumor immunity
Authors: Sabaria Shah, Katherine W Cook, Peter Symonds, Juliane Weißer, Anne Skinner, Abdullah Al Omari, Samantha J Paston, Ian Pike, Lindy G Durrant, Victoria A Brentville
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Post-translational modification of proteins has the potential to alter the ability of T cells to recognize major histocompatibility complex (MHC) class -I and class-II restricted antigens, thereby resulting in altered immune responses. One such modification is carbamylation (homocitrullination) that results in the formation of homocitrulline (Hcit) residues in a non-enzymatic reaction of cyanate with the lysine residues in the polypeptide chain. Homocitrullination occurs in the tumor microenvironment and CD4-mediated immune responses to Hcit epitopes can target stressed tumor cells and provide a potent antitumor response in mouse models. Methods Homocitrullinated peptides were identified and assessed in vitro for HLA-A2 binding and in vivo in human leukocyte antigen (HLA) transgenic mouse models for immunogenicity. CD8 responses were assessed in vitro for cytotoxicity and in vivo tumor therapy. Human tumor samples were analyzed by targeted mass spectrometry for presence of homocitrullinated peptides. Results Homocitrullinated peptides from aldolase and cytokeratin were identified, that stimulated CD8-mediated responses in vivo. Modified peptides showed enhanced binding to HLA-A2 compared with the native sequences and immunization of HLA-A2 transgenic mice generated high avidity modification specific CD8 responses that killed peptide expressing target cells. Importantly, in vivo the homocitrullinated aldolase specific response was associated with efficient CD8 dependent antitumor therapy of the aggressive murine B16 tumor model indicating that this epitope is naturally presented in the tumor. In addition, the homocitrullinated aldolase epitope was also detected in human tumor samples. Conclusion This is the first evidence that homocitrullinated peptides can be processed and presented via MHC-I and targeted for tumor therapy. Thus, Hcit-specific CD8 T-cell responses have potential in the development of future anticancer therapy.
Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma
Authors: Ryan C Augustin, Sarah Newman, Aofei Li, Marion Joy, Maureen Lyons, Mary P Pham, Peter Lucas, Katelyn Smith, Cindy Sander, Brian Isett, Diwakar Davar, Yana G Najjar, Hassane M Zarour, John M Kirkwood, Jason John Luke, Riyue Bao
Journal: Journal for ImmunoTherapy of Cancer (2023)

Acral melanoma (AM) has distinct characteristics as compared with cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICIs). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low versus high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared with responders across cancers, including AM, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.
The enantioselective enhancing effect and mechanistic insights of chiral enhancers in transdermal drug delivery
Authors: Yang Zhang, Chao Liu, Dongxiao E., Wenxuan Jia, Peng Sun, Hui Li, Guojing Yu, Peng Quan, Mingzhe Liu, Liang Fang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects, decreasing therapeutical effects. To improve the transdermal delivery efficiency of eutomer, this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers. Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers. The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer, in which the enhancement effect (ER) of L-menthol on S-enantiomer (ER = 3.23) was higher than that on R-enantiomer (ER = 1.49). According to the pharmacokinetics results, L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer (2.56 fold), and showed excellent in vitro/in vivo correlations. The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention, but the D-isomer by improving partition for better permeation. Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation. Additionally, stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects. In conclusion, enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery, rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects, increasing transdermal therapeutical efficiency.
Editorial Board
Authors: Clarence Loeb, Arthur Proetz, William Wherry, William Benedict, W Morrison, Stanley Truhlsen, Paul Henkind, Paul Lichter, Donald Minckler, Andrew Schachat, George Bartley, Stephen Mcleod, Russell Van Gelder, Seattle Wa, Daniel Albert, St Simons, Creig Hoyt, San Francisco
Journal: Ophthalmology (2023)
Contents
Authors: Arthur Brant, Natasha Kolomeyer, Jeffrey Goldberg, Julia Haller, Cecilia Lee, Aaron Lee, Alice Lorch, Flora Lum, Joan Miller, David Parke, Leslie Hyman, Suzann Pershing, Jeremy Tan, Jack Phu, Denise Go, Doan Morth, Katherine Nguyen, Allan Franzco, Michael Franzco, Ashish Agar, Sooyeon Choe, Young Kim, Woosuk Chung, Donghyun Ko, Marvin Lee, Sung Shim, Ahnul Ha, Anil Mandal, Vijaya Gothwal, Ashik Mohamed, Diane Gibson, Muhammad Chauhan, Abdelrahman Elhusseiny, Paul Phillips
Journal: Ophthalmology (2023)
EASL-ERN position paper on liver involvement in patients with Fontan-type circulation
Authors: Luis Téllez, Audrey Payancé, Eric Tjwa, María Jesús del Cerro, Lars Idorn, Stanislav Ovroutski, Ruth De Bruyne, Henkjan J. Verkade, Fabrizio De Rita, Charlotte de Lange, Annalisa Angelini, Valérie Paradis, Pierre Emmanuel Rautou, Juan Carlos García-Pagán
Journal: Journal of Hepatology (2023)
An Update to the Overview of Reviews: Risks of and From SARS-COV-2 Infection and COVID-19 in People With Diabetes
Authors: Jamie Hartmann-Boyce, Karen Rees, Igho Onakpoya, Afolarin Otunla, Elizabeth Morris, Jessica Morgan, Patrick Highton, Jana Suklan, Ffion Curtis, Clare Goyder, Lauren O’Mahoney, Olivia James, Nayanika Sreejith, Samuel Seidu, Kamlesh Khunti
Journal: Diabetes Care (2023)

In 2020, we were commissioned by the World Health Organization (WHO) to conduct an overview of reviews regarding the extent to which people with diabetes are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or of suffering from its complications.We published this overview in Diabetes Care in 2021 (1).At the request of the WHO, we updated this review with literature through October 2022.Here, we provide readers with a summary of this update.Our 2022 searches identified a further 116 included reviews, a full list and characteristics of which can be found online in the revised supplementary material for the 2021 review (1).We updated our effect direction plots accordingly; these can also be found in the revised supplementary material for readers interested in the data underlying the following summaries.We have notably more data, and updated conclusions, regarding the following points:
Trimethoprim-sulfamethoxazole significantly reduces the risk of nocardiosis in solid organ transplant recipients: systematic review and individual patient data meta-analysis
Authors: Matteo Passerini, Tarek Nayfeh, Zachary A. Yetmar, Julien Coussement, Kellie J. Goodlet, David Lebeaux, Andrea Gori, Maryam Mahmood, Zelalem Temesgen, Mohammad H. Murad
Journal: Clinical Microbiology and Infection (2023)

Whether trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis prevents nocardiosis in solid organ transplant (SOT) recipients is controversial.
AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer
Authors: Olivier Nolan-Stevaux, Cong Li, Lingming Liang, Jinghui Zhan, Juan Estrada, Tao Osgood, Fei Li, Hanzhi Zhang, Ryan Case, Christopher M. Murawsky, Bram Estes, Gregory L. Moore, Matthew J. Bernett, Umesh Muchhal, John R. Desjarlais, Binnaz K. Staley, Jennitte Stevens, Keegan S. Cooke, Famke Aeffner, Oliver Thomas, Julia Stieglmaier, Jae-Lyun Lee, Angela Coxon, Julie M. Bailis
Journal: Cancer Discovery (2023)

The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment. Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5.
Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy
Authors: Nina Zila, Ossia M. Eichhoff, Irene Steiner, Thomas Mohr, Andrea Bileck, Phil F. Cheng, Alexander Leitner, Ludovic Gillet, Tatjana Sajic, Sandra Goetze, Betty Friedrich, Patricia Bortel, Johanna Strobl, René Reitermaier, Sabrina A. Hogan, Julia M. Martínez Gómez, Ramon Staeger, Felix Tuchmann, Sophie Peters, Georg Stary, Mario Kuttke, Adelheid Elbe-Bürger, Christoph Hoeller, Rainer Kunstfeld, Wolfgang Weninger, Bernd Wollscheid, Reinhard Dummer, Lars E. French, Christopher Gerner, Ruedi Aebersold, Mitchell P. Levesque, Verena Paulitschke
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Despite high clinical need, there are no biomarkers that accurately predict the response of patients with metastatic melanoma to anti-PD-1 therapy. Experimental Design: In this multicenter study, we applied protein depletion and enrichment methods prior to various proteomic techniques to analyze a serum discovery cohort (n = 56) and three independent serum validation cohorts (n = 80, n = 12, n = 17). Further validation analyses by literature and survival analysis followed. Results: We identified several significantly regulated proteins as well as biological processes such as neutrophil degranulation, cell–substrate adhesion, and extracellular matrix organization. Analysis of the three independent serum validation cohorts confirmed the significant differences between responders (R) and nonresponders (NR) observed in the initial discovery cohort. In addition, literature-based validation highlighted 30 markers overlapping with previously published signatures. Survival analysis using the TCGA database showed that overexpression of 17 of the markers we identified correlated with lower overall survival in patients with melanoma. Conclusions: Ultimately, this multilayered serum analysis led to a potential marker signature with 10 key markers significantly altered in at least two independent serum cohorts: CRP, LYVE1, SAA2, C1RL, CFHR3, LBP, LDHB, S100A8, S100A9, and SAA1, which will serve as the basis for further investigation. In addition to patient serum, we analyzed primary melanoma tumor cells from NR and found a potential marker signature with four key markers: LAMC1, PXDN, SERPINE1, and VCAN.
Key Risk Factors Associated With Electronic Nicotine Delivery Systems Use Among Adolescents
Authors: Thuy T. T. Le
Journal: JAMA Network Open (2023)

Importance The prevalence of electronic nicotine delivery systems (ENDS) use among US youths has increased significantly during the past decade. Identifying key factors highly associated with ENDS use is essential in monitoring and preventing this harmful behavior among youths. Objective To identify the most important risk factors in wave 4.5 (ie, December 2017 to December 2018) of the Population Assessment of Tobacco and Health Study (PATH) data that are associated with ENDS use in wave 5 (ie, December 2018 to November 2019) among adolescents who were tobacco-naive at baseline. Design, Setting, and Participants This prognostic study examined data from waves 4.5 and 5 of the PATH youth data set using machine learning techniques. The PATH study is a nationally representative longitudinal cohort study of tobacco use and health in the United States among individuals aged 12 years and older. The data analysis was carried out between January and April 2023. Main Outcomes and Measures Wave 5 current ENDS use status of wave 4.5 adolescents who were tobacco-naive. Results The analyzed data set comprised 7943 individuals who were tobacco-naive in wave 4.5. Among this group, 332 participants (4.2%) indicated their present use of ENDS in wave 5, 5047 (63.5%) were aged 12 to 14 years, 4066 (51.2%) were male, and 2455 (30.9%) were Hispanic. The most important risk factors of ENDS use in wave 5 among adolescents who were tobacco-naive in wave 4.5 were the likelihood of using ENDS if offered by a best friend (mean SHAP value, 0.184), the number of best friends using e-cigarettes (mean SHAP value, 0.167), household tobacco usage (mean SHAP value, 0.161), curiosity about ENDS use (mean SHAP value, 0.088), future intention to use ENDS (mean SHAP value, 0.068), youth’s total average weekly earnings (mean SHAP value, 0.060), and perceptions of tobacco product safety (mean SHAP value, 0.026). Conclusions and Relevance The findings of this study suggest that family and friends play an important role in ENDS use among adolescents. The top-ranking factors associated with ENDS use in this study are areas for further exploration, given the increasing prevalence of ENDS use among youths in recent years. Additionally, these findings highlight the important role of families and schools in shaping adolescents’ tobacco-related knowledge, which can protect them from using ENDS.
Temporal Enzymatic Treatment to Enhance the Remodeling of Multiple Cartilage Microtissues into a Structurally Organized Tissue
Authors: Ross Burdis, Xavier Barceló Gallostra, Daniel J. Kelly
Journal: Advanced Healthcare Materials (2023)

Scaffold-free tissue engineering aims to recapitulate key aspects of normal developmental processes to generate biomimetic grafts. Although functional cartilaginous tissues are engineered using such approaches, considerable challenges remain. Herein, the benefits of engineering cartilage via the fusion of multiple cartilage microtissues compared to using (millions of) individual cells to generate a cartilaginous graft are demonstrated. Key advantages include the generation of a richer extracellular matrix, more hyaline-like cartilage phenotype, and superior shape fidelity. A major drawback of aggregate engineering is that individual microtissues do not completely (re)model and remnants of their initial architectures remain throughout the macrotissue. To address this, a temporal enzymatic (chondroitinase-ABC) treatment is implemented to accelerate structural (re)modeling and shown to support robust fusion between adjacent microtissues, enhance microtissue (re)modeling, and enable the development of a more biomimetic tissue with a zonally organized collagen network. Additionally, enzymatic treatment is shown to modulate matrix composition, tissue phenotype, and to a lesser extent, tissue mechanics. This work demonstrates that microtissue self-organization is an effective method for engineering scaled-up cartilage grafts with a predefined geometry and near-native levels of matrix accumulation. Importantly, key limitations associated with using biological building blocks can be alleviated by temporal enzymatic treatment during graft development.